International observational atopic dermatitis cohort to follow natural history and treatment course: TARGET-DERM AD study design and rationale

INTRODUCTION: As new topical and systemic treatments become available for atopic dermatitis (AD), there is a need to understand how treatments are being used in routine clinical practice, their comparative effectiveness and their long-term safety in diverse clinical settings. METHODS AND ANALYSIS: The TARGET-DERM AD cohort is a longitudinal, observational study of patients with AD of all ages, designed to provide practical information on long-term effectiveness and safety unobtainable in traditional registration trials. Patients with physician-diagnosed AD receiving prescription treatment (topical or systemic) will be enrolled at academic and community clinical centres. Up to 3 years of retrospective medical records, 5 years of prospective medical records, and optional biological samples and patient-reported outcomes will be collected. The primary aims include characterisation of AD treatment regimens, evaluation of response to therapy, and description of adverse events. ETHICS AND DISSEMINATION: TARGET-DERM has been approved by a central IRB (Copernicus Group IRB, 5000 Centregreen Way Suite 200, Cary, North Carolina 27513) as well as local and institutional IRBs. No additional Ethics Committee reviews. Results will be reviewed by a publications committee and submitted to peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03661866, pre-results

Observation of Two Excited B-c(+) States and Measurement of the B-c(+) (2S) Mass in pp Collisions at root s=13 TeV

Signals consistent with the B-c(+)(2S) and B-c*(+)(2S) states are observed in proton-proton collisions at root s = 13 TeV, in an event sample corresponding to an integrated luminosity of 143 fb(-1), collected by the CMS experiment during the 2015-2018 LHC running periods. These excited (b) over barc states are observed in the B-c(+)pi(+)pi(-) invariant mass spectrum, with the ground state B-c(+) reconstructed through its decay to J/psi pi(+). The two states are reconstructed as two well-resolved peaks, separated in mass by 29.1 +/- 1.5(stat) +/- 0.7(syst) MeV. The observation of two peaks, rather than one, is established with a significance exceeding five standard deviations. The mass of the B-c(+)(2S) meson is measured to be 6871.0 +/- 1.2(stat) +/- 0.8(syst) +/- 0.8(B-c(+)) MeV, where the last term corresponds to the uncertainty in the world-average B-c(+) mass.Peer reviewe

Evidence for light-by-light scattering and searches for axion-like particles in ultraperipheral PbPb collisions at root s(NN)=5.02 TeV

Evidence for the light-by-light scattering process, gamma gamma -> gamma gamma, in ultraperipheral PbPb collisions at a centre-of-mass energy per nucleon pair of 5.02 TeV is reported. The analysis is conducted using a data sample corresponding to an integrated luminosity of 390 mu b(-1) recorded by the CMS experiment at the LHC. Light-by-light scattering processes are selected in events with two photons exclusively produced, each with transverse energy E-T(gamma) > 2 GeV, pseudorapidity vertical bar eta(gamma)vertical bar 5 GeV, diphoton transverse momentum p(T)(gamma gamma) gamma gamma) = 120 +/- 46(stat) +/- 28(syst) +/- 12(theo) nb, is consistent with the standard model prediction. The m(gamma gamma) distribution is used to set new exclusion limits on the production of pseudoscalar axion-like particles, via the gamma gamma -> a -> gamma gamma process, in the mass range m(a) = 5-90 GeV. (C) 2019 The Author(s). Published by Elsevier B.V.Peer reviewe

JC Polyomavirus Infection Is Strongly Controlled by Human Leucocyte Antigen Class II Variants

JC polyomavirus (JCV) carriers with a compromised immune system, such as in HIV, or subjects on immune-modulating therapies, such as anti VLA-4 therapy may develop progressive multifocal leukoencephalopathy (PML) which is a lytic infection of oligodendrocytes in the brain. Serum antibodies to JCV mark infection occur only in 50-60% of infected individuals, and high JCV-antibody titers seem to increase the risk of developing PML. We here investigated the role of human leukocyte antigen (HLA), instrumental in immune defense in JCV antibody response. Anti-JCV antibody status, as a surrogate for JCV infection, were compared to HLA class I and II alleles in 1621 Scandinavian persons with MS and 1064 population-based Swedish controls and associations were replicated in 718 German persons with MS. HLA-alleles were determined by SNP imputation, sequence specific (SSP) kits and a reverse PCR sequence-specific oligonucleotide (PCR-SSO) method. An initial GWAS screen displayed a strong HLA class II region signal. The HLA-DRB1*15 haplotype was strongly negatively associated to JCV sero-status in Scandinavian MS cases (OR\u200a=\u200a0.42, p\u200a=\u200a7 710(-15)) and controls (OR\u200a=\u200a0.53, p\u200a=\u200a2 710(-5)). In contrast, the DQB1*06:03 haplotype was positively associated with JCV sero-status, in Scandinavian MS cases (OR\u200a=\u200a1.63, p\u200a=\u200a0.006), and controls (OR\u200a=\u200a2.69, p\u200a=\u200a1 710(-5)). The German dataset confirmed these findings (OR\u200a=\u200a0.54, p\u200a=\u200a1 710(-4) and OR\u200a=\u200a1.58, p\u200a=\u200a0.03 respectively for these haplotypes). HLA class II restricted immune responses, and hence CD4+ T cell immunity is pivotal for JCV infection control. Alleles within the HLA-DR1*15 haplotype are associated with a protective effect on JCV infection. Alleles within the DQB1*06:03 haplotype show an opposite association. These associations between JC virus antibody response and human leucocyte antigens supports the notion that CD4+ T cells are crucial in the immune defence to JCV and lays the ground for risk stratification for PML and development of therapy and prevention

Author Correction: A systems biology approach uncovers cell-specific gene regulatory effects of genetic associations in multiple sclerosis.

An amendment to this paper has been published and can be accessed via a link at the top of the paper

CYTOTOXIC DIAMINE-PLATINUM(II) COMPLEXES WITH METHYLSULFINYL CARBOXYLATES AS THE LEAVING GROUPS - SYNTHESIS, CHARACTERIZATION, AND REACTIVITY TOWARD CHLORIDE-IONS, 5'-GMP, AND 9-METHYLGUANINE

Compounds of formula [Pt(diam)(Soa)]NO3, 3, and [Pt(diam)(Sob)]NO3, 4, (Soa, (methylsulfinyl)acetate; Sob, 2-(methylsulfinyl)benzoate; diam, chelating diamines: 1,2-ethylenediamine, en; (+/-)-, R,R-, S,S-, and meso-1,2-diaminocyclohexane, dach; 1,1-bis(aminomethyl)cyclohexane, damch) have been synthesized. IR, NMR, and FAB-mass spectroscopy suggest that the Soa and Sob anions are chelated to Pt through the S atom and the carboxylate group. Such a mode of coordination was confirmed for compounds 3 by the X-ray crystal structure determination of [Pt(en)(Soa)]NO3. This compound crystallizes in space group R3 (No. 146) with cell constants a = 15.139(3) angstrom and c = 12.886(2) angstrom. The structure was refined using 1001 independent reflections with I > 3sigma(I), giving a final R value of 0.018. In the complex cation Pt is in a square planar environment with en (Pt-N, 2.019(8) and 2.055(8) angstrom) and Soa (Pt-S, 2.184(2) angstrom, and Pt-O, 2.025(6) angstrom) chelated to Pt. The reactivities of 3 and 4 toward Cl-, 5'-GMP, and 9-methylguanine have been investigated by H-1 NMR spectroscopy at 40-degrees-C and complex concentration 10(-2) mol L-1 in D2O. Compounds 3 react readily with Cl- by displacement of the carboxylate group, yielding [PtCl(diam)(Soa-S)] (with monodentate S-coordinated Soa) which reacts with excess chloride to give [PtCl2-(diam)] at a very slow rate (for the en derivative formation of [PtCl2(en)] 24 h, but the concentration of the intermediates with S-coordinated monodentate Sob remains very low throughout the course of the reaction, indicating that the Sob chelate ring is more inert toward ring opening. Reactions of 3 and 4 toward 5'-GMP are rather fast: formation of [Pt(dach)(GMP)2]2- is complete in 3 and 1 h respectively (Pt/GMP = 1/2). These reactions proceed via the formation of intermediates with one N(7)-bound GMP and one monodentate Soa, coordinated to Pt via the S atom, or Sob probably bound to Pt via the O (sulfinyl) atom. Reactions with 9-methylguanine are slower and occur with a similar mechanism. The first step of the reaction of 5 with 2 mol of GMP is displacement of Cl by GMP. Formation of [Pt(en)(GMP)2]2- is complete in 75 min. Complexes 3 and 4 are moderately cytotoxic toward L1210 leukemia cells; the dach and damch derivatives are cytotoxic also against the L1210 cisplatin-resistant line. The cytotoxicities of the dach complexes depend not only on the absolute configuration of the diamine, but also on the configuration of the leaving group

Gold branched nanoparticles for cellular treatments

Under the action of near-infrared radiation, shape anisotropic gold nanoparticles emit two-photon luminescence and release heat. Accordingly, they have been proposed for imaging, photothermal therapies and thermo-controlled drug delivery. In all these applications particular care must be given to control the nanoparticle - cell interaction and the thermal efficiency of the nanoparticles, while minimizing their intrinsic cytotoxicity. We present here the characterization of the cell interaction of newly developed branched gold nanostars, obtained by laurylsulfobetaine-driven seed-growth synthesis. The study provides information on the size distribution, the shape anisotropy, the cellular uptake and cytotoxicity of the gold nanostars as well as their intracellular dynamic behavior by means of two-photon luminescence imaging, fluorescence correlation spectroscopy and particle tracking. The results show that the gold nanostars are internalized as well as the widely used gold nanorods and are less toxic under prolonged treatments. At the same time they display remarkable two-photon luminescence and large extinction under polarized light in the near-infrared region of the spectrum, 800-950 nm. Gold nanostars appear then a valuable alternative to other elongated or in-homogeneous nanoparticles for cell imaging. © 2012 American Chemical Society